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IκB-ζ Expression Requires Both TYK2/STAT3 Activity and IL-17–Regulated mRNA Stabilization

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Title: IκB-ζ Expression Requires Both TYK2/STAT3 Activity and IL-17–Regulated mRNA Stabilization
Authors: Muromoto, Ryuta Browse this author →KAKEN DB
Tawa, Keisuke Browse this author
Ohgakiuchi, Yui Browse this author
Sato, Ami Browse this author
Saino, Yuka Browse this author
Hirashima, Koki Browse this author
Minoguchi, Hiroya Browse this author
Kitai, Yuichi Browse this author →KAKEN DB
Kashiwakura, Jun-ichi Browse this author →KAKEN DB
Shimoda, Kazuya Browse this author →KAKEN DB
Oritani, Kenji Browse this author →KAKEN DB
Matsuda, Tadashi Browse this author →KAKEN DB
Issue Date: 16-May-2019
Publisher: The American Association of Immunologists
Journal Title: ImmunoHorizons
Volume: 3
Issue: 5
Start Page: 172
End Page: 185
Publisher DOI: 10.4049/immunohorizons.1900023
Abstract: Cytokine IL-17A (IL-17) acts on various cell types, including epidermal keratinocytes, and induces antimicrobial peptide and chemokine production to elicit antibacterial and antifungal defense responses. Excess IL-17 leads to inflammatory skin diseases such as psoriasis. The IκB family protein IκB-ζ mediates IL-17–induced responses. However, the mechanism controlling IκB-ζ expression in IL-17–stimulated cells remains elusive. In this study, we showed that JAK kinase TYK2 positively regulates IL-17–induced IκB-ζ expression. TYK2-deficient mice showed reduced inflammation and concomitant reduction of IκB-ζ mRNA compared with wild-type mice in imiquimod-induced skin inflammation. The analysis of the IκB-ζ promoter activity using human cell lines (HaCaT and HeLa) revealed that catalytic activity of TYK2 and its substrate transcription factor STAT3, but not IL-17, is required for IκB-ζ promoter activity. In contrast, IL-17–induced signaling, which did not activate STAT3, posttranscriptionally stabilized IκB-ζ mRNA via its 3′-untranslated region. IL-17 signaling protein ACT1 was required to counteract constitutive IκB-ζ mRNA degradation by RNase Regnase-1. These results suggested that transcriptional activation by TYK2–STAT3 pathway and mRNA stabilization by IL-17–mediated signals act separately from each other but complementarily to achieve IκB-ζ induction. Therefore, JAK/TYK2 inhibition might be of significance in regulation of IL-17–induced inflammatory reactions.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 松田 正

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